N-Methyl-imidazole derivatives for treating mycotic infections

ABSTRACT

N-methyl-imidazole derivatives of the formula: ##EQU1## or a pharmaceutically acceptable non-toxic salt thereof, wherein X is an unsubstituted or substituted 6-membered heteroaromatic moiety having two nitro heteroatoms, 
     Y is an unsubstituted or substituted aliphatic moiety, an unsubstituted or substituted cycloaliphatic moiety, an unsubstituted or substituted aralkyl moiety or an unsubstituted or substituted aryl moiety, and 
     Z is an unsubstituted or substituted aliphatic moiety, an unsubstituted or substituted cycloaliphatic moiety, an unsubstituted or substituted aralkyl moiety, an unsubstituted or substituted aryl moiety, an unsubstituted or substituted pyridyl moiety or an alkoxycarbonyl moiety, 
     Are useful as antimycotic agents.

This is a division of application Ser. No. 474,873 filed May 31, 1974which is a division of Ser. No. 310,423 filed Nov. 29, 1972 which is adivision of Ser. No. 120,333 filed Mar. 2, 1971 now U.S. Pat. No.3,787,415, issued Jan. 22, 1974.

The present invention is concerned with N-methyl-imidazole derivativesand this production as well as with pharmaceutical compositions, whereinsaid N-methyl-imidazole derivatives are the active ingredient and withmethods of treating mycotic infections which comprises administering theN-methyl-imidazole derivatives of the present invention.

More particularly, the present invention is concerned withN-methyl-imidazole derivatives which are substituted at the methylcarbon atom by a 6-membered heterocyclic moiety having two ring nitrogenatoms. These compounds are particularly useful for their antimycotic andfungitoxic activity.

Some derivatives of 6-membered heterocyclic compounds, which contain twonitrogen atoms in the nucleus, are known. U.S. Pat. No. 2,839,446describes pyrimidies which carry a trichloromethylsulphonyl group in the2-position as being leaf fungicides. Netherlands patent specificationNo. 6,806,106 describes 5-substituted pyrimidines carrying adisubstituted or trisubstituted methyl group as the substituent, itbeing possible for one of the substituents on this methyl group to be ahydroxyl, amino or phenylamino group. The pyrimidyl-diaryl-carbinols, inparticular, represent valuable systematic plant fungicides. Thesepreviously known compounds are however all exclusively active againstplant-pathogenic fungi and bacteria.

N-trityl-imidazole and substituted N-trityl-imidazoles are referred toin U.S. Pat. No. 3,321,366 as being useful against plant fungi.

The compounds of the present invention may be represented by theformula: ##EQU2## wherein

X is an unsubstituted or substituted 6-membered heteroaromatic moietyhaving two nitro heteroatoms,

Y is an unsubstituted or substituted aliphatic moiety, an unsubstitutedor substituted cycloaliphatic moiety, an unsubstituted or substitutedaralkyl moiety or an unsubstituted or substituted aryl moiety, and

Z is an unsubstituted or substituted aliphatic moiety, an unsubstitutedor substituted cycloaliphatic moiety, an unsubstituted or substitutedaralkyl moiety, an unsubstituted or substituted aryl moiety, anunsubstituted or substituted pyridyl moiety or an alkoxycarbonyl moiety,

and include pharmaceutically acceptable non-toxic salts thereof.

Among the heteraromatic moieties for X are those of the formula:##SPC1##

which are bonded to the central carbon atom of formula (I) via a carbonatom in the ring and can either be unsubstituted or may be substitutedby 1 to 3, and preferably 1 or 2 substituents which can either be thesame or different. Suitable substituents include halogen, particularlyfluorine, chlorine and bromine, and especially chlorine, alkyl of 1 to 4carbon atoms, and preferably 1 or 2 carbon atoms, alkoxy of 1 to 4carbon atoms, and preferably 1 or 2 carbon atoms or phenyl. Among theabove alkyl and alkoxy substituents are methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert. butyl, particularly methyl andethyl, and methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxyand tert. butoxy, especially methoxy and ethoxy. If X is a pyridazinering, it is preferably bonded in the 4-position to the central carbonatom. If R is a pyrimidine ring, it is preferred that it be bonded inthe 2- or 5-position to the central carbon atom.

When Y and/or Z are unsubstituted or substituted aliphatic moieties, itis preferred that such aliphatic moieties be straight or branched chainalkyl of 1 to 6 carbon atoms, and especially 1 to 4 carbon atoms,particularly methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl andtert. butyl, particularly methyl and tert. butyl. When such aliphaticmoieties are substituted, it is preferred that there be one or moresubstituents, and preferably one or two substituents. Suitablesubstituents are alkyl of 1 to 4 carbon atoms, and preferably 1 or 2carbon atoms, alkoxy of 1 to 4 carbon atoms, and preferably 1 or 2carbon atoms, thioalkyl of 1 to 4 carbon atoms, and preferably 1 or 2carbon atoms, trifluoromethyl, halogen, especially fluorine, chlorine orbromine, nitro and cyano. Particular alkyl, alkoxy and thioalkylmoieties include methyl, ethyl, methoxy, ethoxy, methylmercapto, i.e.thiomethyl and ethylmercapto, i.e. thioethyl.

When X and/or Z are unsubstituted or substituted cycloaliphaticmoieties, it is preferred that these have 3 to 8 carbon atoms, andespecially 3 to 6 carbon atoms. Cyclopropyl and cyclohexyl are preferredmoieties. When the cycloaliphatic moieties are substituted, it ispreferred that there are one or more substituents and preferably one ortwo substituents. Suitable substituents include alkyl of 1 to 4 carbonatoms, preferably 1 or 2 carbon atoms, alkoxy of 1 to 4 carbon atoms,preferably 1 or 2 carbon atoms, thioalkyl of 1 to 4 carbon atoms,preferably 1 or 2 carbon atoms, trifluoromethyl, halogen, especiallyfluorine, chlorine or bromine, nitro and cyano. Among the alkyl, alkoxyand thialkyl moieties are methyl, ethyl, methoxy, ethoxy, methylmercaptoand ethylmercapto.

When Y and/or Z are unsubstituted or substituted aralkyl moieties, it ispreferred that these have 6 to 12 carbon atoms, and especially 6 carbonatoms in the aryl portion, and 1 to 4 carbon atoms, and especially 1 or2 carbon atoms in the alkyl portion. Benzyl and p-chlorobenzyl are amongthe preferred substituents. When the aralkyl moiety is substituted,there can be one or more substituents, preferably one or two.Substituents include alkyl of 1 to 4 carbon atoms, preferably 1 or 2carbon atoms, alkoxy of 1 to 4 carbon atoms, preferably 1 or 2 carbonatoms, thioalkyl of 1 to 4 carbon atoms, preferably 1 or 2 carbon atoms,trifluoromethyl, halogen, especially fluorine, chlorine or bromine,nitro and cyano. Among the alkyl, alkoxy and thialkyl moieties aremethyl, ethyl, methoxy, ethoxy, methylmercapto and ethylmercapto.

When Y and/or Z are unsubstituted or substituted aryl moieties, it ispreferred that these have 6 to 10 carbon atoms, and especially 6 carbonatoms. When the aryl moiety is substituted, there can be one or moresubstituents, preferably 1 or 2. Substituents include alkyl of 1 to 4carbon atoms, preferably 1 or 2 carbon atoms, alkoxy of 1 to 4 carbonatoms, preferably 1 or 2 carbon atoms, thioalkyl of 1 to 4 carbon atoms,preferably 1 or 2 carbon atoms, trifluoromethyl, halogen, especiallyfluorine, chlorine or bromine, nitro and cyano. Among the alkyl, alkoxyand thioalkyl moieties are methyl, ethyl, methoxy, ethoxy,methylmercapto and ethylmercapto.

The preferred aryl moieties are phenyl, p-fluorophenyl, o-chlorophenyl,o-methylphenyl, o-isopropylphenyl, p-methoxyphenyl,m-trifluoromethylphenyl, m-nitrophenyl and naphthyl.

When Z is an unsubstituted or substituted pyridyl moiety, the pyridylmoiety is bonded in the 2-, 3- or 4-position to the central carbon atom.When the pyridyl moiety is substituted, it can contain one or moresubstituents, and preferably 1 or 2 substituents. Suitable substituentsinclude alkyl of 1 to 4 carbon atoms, preferably 1 or 2 carbon atoms,alkoxy of 1 to 4 carbon atoms, preferably 1 or 2 carbon atoms, thioalkylof 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms, trifluoromethyl,halogen, especially fluorine, chlorine and bromine, nitro and cyano.Among the alkyl, alkoxy and thioalkyl moieties are methyl, ethyl,methoxy, ethoxy, methylmercapto and ethylmercapto. When Z is pyridyl, itis preferred that the pyridyl moiety be unsubstituted.

When Z is alkoxycarbonyl, it is preferred that there be 1 to 4 carbonatoms, and especially 1 or 2 carbon atoms, in the alkyl moiety.Methoxycarbonyl and ethoxycarbonyl are preferred.

Preferred salts of the compounds of the present invention are thosewhich are formed with pharmaceutically acceptable non-toxic acids, i.e.those which are physiologically well tolerated. Examples of such acidsare the hydrogen halide acids, such as for example hydrobromic acid andhydrochloric acid, phosphoric acids, sulphonic acids, monocarboxylic anddicarboxylic acids and hydroxycarboxylic acids. As examples of organicacids, acetic acid, tartaric acid, lactic acid, malic acid, citric acid,salicyclic acid, sorbic acid and ascorbic acid may be mentioned.

Particularly preferred compounds are those of the formula (I)

in which

X is a 6-membered heteroaromatic ring of the formula: ##SPC2##

Y is phenyl or p-fluorophenyl, and

Z is phenyl and pharmaceutically acceptable non-toxic salts thereof.

The compounds of the present invention can be produced according toseveral processes. According to one process, the compounds of thepresent invention are produced if

a) a compound of the formula ##EQU3## wherein

Hal is Cl or Br,

is reacted with imidazole, optionally in the presence of an acidacceptor or in the presence of an excess of imidazole in a polar organicsolvent at temperatures between about 20° and about 150° C, and the saltis optionally manufactured, or

b) a carbinol of the formula: ##EQU4## wherein

X, Y and Z are as above defined, is reacted with thionyldiimidazole offormula ##SPC3##

in an aprotic solvent, and the salt is optionally manufactured.

The starting compounds required for the manufacture of the new compounds(I) are known or are obtainable according to known processes.

The compounds (II) can be manufactured in various ways. For example, itis possible to start from a carbinol (III) and to react this with ahalogenating agent, such as for example thionyl chloride, thionylbromide, phosphoryl chloride, phosphoryl bromide, acetyl chloride oracetyl bromide, in solvents, such as for example ether, methylenechloride, benzene or toluene. It may at times also be appropriate tocarry out the halogenation in a polar solvent and to follow thisdirectly by the reaction with imidazole, without intermediate isolationof the halide formed. As polar organic solvents, acetonitrilenitromethane, dimethylformamide or hexamethylphosphoric acid triamidemay for example be mentioned.

A further process for the manufacture of compounds of the formula (II),in which Hal is chlorine and X and Y are as above defined, comprisesreacting a ketone of the formula: ##EQU5## in which

X and Y are as above defined, firstly with PCl₅ to give a dichloride ofthe formula: ##EQU6## wherein X and Y are as above defined.

This dichloride is subsequently reacted with an optionally substitutedaromatic compound, in the presence of at least one equivalent ofaluminium chloride, to give the chloride (II).

An excess of the aromatic compound, or some other solvent suitable forthis reaction, such as for example carbon disulphide, can be used as thesolvent in this Friedel-Crafts reaction.

A further process for the manufacture of the halides (II) consists ofreacting a methane derivative of the formula ##EQU7## in which

X, Y and Z have the abovementioned meaning, with a halogenating agentwhich operates by a radical mechanism such as for exampleN-chlorophthalimide or N-bromosuccinimide, in an inert organic solvent,such as for example carbon tetrachloride.

The starting substances required for the processes indicated are knownor can be manufactured analogously to known processes. For example,2-diphenylmethylpyrazine is obtained according to a method described inBehun et al, J. Org. Chem. 26, 3379 (1961). Further pyrazylcarbinolshave been described by Hirschberg, J. Heterocyclic Chem. 2, 209 (1965).Further, pyrazine derivatives which can be used as starting substancesof general formulae (II), (III) and (VII), in which X represents apyrazine radical, for the manufacture of compounds of formula (I), inwhich X is a pyrazine radical, are described in Netherlands patentspecification No. 105,432 and in German Displayed Specification No.1,913,726.

Pyrimidine compounds of the formula (II), (III) and (VII), in which X ispyrimidine, used as starting substances, are also known or can bemanufactured according to processes which are in themselves known.Several processes are for example given in Chem. Ber. 93, 230 (1960) andin Netherlands patent application No. 6,806,106.

Pyridazine compounds of the formula (II), (III) and (VII), in which X ispyridazine, can also be obtained in an analogous manner to thatdescribed in the abovementioned publications.

In process variant a) the starting compound (II), the imidazole and theacid acceptor are employed in about molar amounts. If an excess ofimidazole is added as the acid acceptor, about 2 mols of imidazole mustbe used for this reaction. The reaction temperature is about 20° toabout 150°C, preferably about 60° to about 100°C.

As solvents in process a), polar organic solvents, such as for examplelower alkylnitriles, such as for example acetonitrile,dimethylformamide, dimethylsulphoxide, lower alkylketones, such as forexample diethyl ketone, and hexamethyl phosphoric acid triamide can beused.

Inorganic and organic bases can serve as acid acceptors. As inorganicbases, the alkali carbonates and alkaline earth carbonates, especiallypotassium carbonate and calcium carbonate, may for example be used. Asorganic bases, lower alkylamines, such as for example triethylamine, aswell as hetero-aromtic bases, such as for example pyridine and lutidinemay for example be used.

In process variant b), the reactants (III) and (IV) are employed inabout molar amounts. Preferably, however, about 1 to about 2 mols ofthionyldiimidazole (IV) are employed per 1 mol of carbinol (III). Thereaction temperature is about 0° to about 100°C, preferably about 20° toabout 50°C.

The reaction b) is generally carried out in inert organic solvents, suchas for example lower alkylnitriles, such as for example acetonitrile,ethers, such as for example tetrahydrofurane and diisopropyl ether,dimethylformamide or chlorinated hydrocarbons, such as for examplechloroform.

If 2-isopropyl-phenyl-2-pyrazyl-carbinol is used as the startingmaterial, the course of the reaction according to process a) can berepresented by the following equation: ##SPC4##

The course of the reaction of process b) can be represented by thefollowing equation for the example of the reaction oftert.-butyl-phenyo-5-pyrimidyl-carbinol with thionyldiimidazole:##SPC5##

The following non-limitative examples more particularly illustrate thepresent invention.

EXAMPLE 1 Diphenyl-pyrimid-5-yl-imidazol-1-yl-methane.

26.2 g (0.1 mole) of diphenyl-pyrimid-5-yl-carbinol, melting point161°C, are treated with a solution of 0.15 mol of thionyldiimidazole in200 ml of dry acetonitrile and the mixture is heated to the boil for 10minutes. Thereafter it is cooled, diluted with ice water and filtered.The residue is washed with water. 23.6g (76% of theory) of a white,finely crystalline substance of formula ##SPC6##

of melting point 209°C are obtained.

Analysis: C₂₀ H₁₆ N₄ (312.36). Calculated: C, 76.9%; H, 5.2%; N,17.9%.Found: C, 77.3%; H,5.6%; N,18.0%.

The thionyldiimidazole used for the reaction is obtainable as follows:

40.8 g (0.6mol) of imidazole dried over P₂ O₅ are suspended in 150 ml ofacetonitrile distilled over P₂ O₅ and treated, at 0°C, with 17.7 g(0.15mol) of freshly distilled thionyl chloride. The imidazolehydrochloride which has precipitated is rapidly filtered off and rinsedwith 50 ml of acetonitrile. The filtrate is immediately used for thereaction.

EXAMPLE 2 Diphenyl-pyrazyl-imidazol-1-yl-methane.

26.2 g (0.1 mol) of diphenyl-pyrazyl-carbinol, melting point 111°C, aretreated with a solution of 0.15 mol of thionyl diimidazole in 200 ml ofdry acetonitrile and the mixture is heated under reflux for 1 hour.Thereafter it is concentrated and the oily-crystalline residue is washedwith water. 7.2 g of a light brown crude product are obtained, whichafter recrystallisation from ether/acetone yield 8.8 g (28 % of theory)of a compound of the formula ##SPC7##

in the form of white crystals of melting point 198°C.

Analysis: C₂₀ H₁₆ N₄ (312.36). Calculated: C, 76.9%; H, 5.2%; N, 17.9%.Found: C, 76.9%; H, 5.5%; N, 18.0%.

EXAMPLE 3 4-Fluorophenyl-phenyl-pyrazyl-imidazol-1-yl-methane

28.0 g (0.1 mol) of 4-fluorophenyl-phenyl-pyrazylcarbinol together witha solution of 0.15 mol of thionylidiimidazole in 200 ml of acetonitrileare heated to the boil for 1 hour. Thereafter the mixture is filteredand concentrated, the residue is taken up in methylene chloride and thesolution is repeatedly extracted by shaking with water. The methylenechloride phase is dried and concentrated. A brown oil is obtained, whichis taken up in acetonitrile. After treating the solution with activecharcoal and filtering, dry hydrogen chloride is passed in untilsaturation is reached, and the precipitated product is filtered off andrinsed with acetonitrile and ether. 12.7 g (35% of theory) of thecompound of formula ##SPC8##

are obtained in the form of a yellow, hydroscopic powder of meltingpoint 86°C (decomposition).

Analysis: C₂₀ H₁₅ FN₄ . HCl (366.81). Calculated: N, 15.3%; Cl, 9.7%;Found: N, 14.8%; Cl, 9.9%;

EXAMPLE 4 Diphenyl-4,5,6-trichloropyrimid-2-yl-imidazol-1-yl-methane

34.0 g (0.1 mol) of diphenyl-4,5,6-trichloropyrimid-2-yl-chloromethanein 250 ml of absolute acetonitrile are stirred with 13.6 g (0.2 mol) ofimidazole for 3 hours at room temperature and thereafter heated to theboil for 15 minutes. The mixture is then concentrated and the dark brownresidue is washed with water and taken up in methylene chloride. Afterdrying with sodium sulphate, treating with active charcoal andfiltering, the solution is concentrated. The residue is extracted byboiling with petroleum ether, and the mixture is filtered and againconcentrated. Finally, the material is recrystallised from a littleacetonitrile. 17.0 g (40% of theory) of the compound of formula ##SPC9##

are obtained in the form of orange-coloured crystals of melting point142° - 146° C.

EXAMPLE 5 Diphenyl-pyrimid-2-yl-imidazol-1-yl-methane

26.2 g (0.1 mol) of diphenyl-pyrimid-2-yl-carbinol are dissolved in 100ml of absolute acetonitrile and treated with a solution of 0.15 mol ofthionyldiimidazole in 200 ml of acetonitrile. The mixture is stirred forone hour at room temperature and subsequently heated to the boil for 10minutes. It is then concentrated to about half its volume and dilutedwith ice water. The yellow oil which has precipitated is washed withwater, taken up in methylene chloride and the solution dried. Afterconcentration, a viscous residue remains which slowly crystallises. 16.0g (41% of theory) of the compound of formula ##SPC10##

are thus obtained, having a melting point of 138° - 143° C.

The following compounds, wherein X, Y and Z of the below set forthformula are as indicated, are produced in a manner analogous to that ofthe preceding examples from the reactants set forth in the table whichfollows: ##SPC11## ##SPC12## ##SPC13##

                  Table                                                           ______________________________________                                               process a)     process b)                                                     (see pages 7-8)                                                                              (see pages 7-8)                                                reactants:     reactants:                                              Example                                                                       No.    A              B                                                       ______________________________________                                               Z         (meaning      Z                                                     |                                                                              of X,Y,Z      |                                      6     Y--C--Cl  for each      Y--C--OH                                              |                                                                              example       |                                            X         see pages     X                                                               17-19)                                                        7     "                       "                                               8     "                       "                                               9     "                       "                                              10     "                       "                                              11     "                       "                                              12     "                       "                                                     Z                                                                             |                                                             13     Y--C--Br                "                                                     |                                                                    X                                                                      14     "                       "                                              15     "                       "                                              16     "                       "                                              17     "                       "                                              18     "                       "                                              19     "                       "                                              20     "                       "                                                     Z                                                                             |                                                             21     Y--C--Cl                "                                                     |                                                                    X                                                                      22     "                       "                                              23     "                       "                                              24     "                       "                                              25     "                       "                                              26     "                       "                                              27     "                       "                                              ______________________________________                                    

As already mentioned, the new compounds show an excellent anti-mycoticactivity, as can be seen from the following in vitro and in vivoexperiments:

a. Anti-mycotic action in vitro.

The Table summarises the anti-mycotic actions in vitro of severalpreparations towards several species of fungi:

    ______________________________________                                        Minimal inhibitory concentration (MIC)                                        in γ/ml of substrate                                                           Tricho-                                                                Compound                                                                             phyton   Micro-          Asper-                                        from   menta-   sporon   Candida                                                                              gillus                                                                              Penicillium                             example                                                                              grophytes                                                                              felineum albicans                                                                             niger commune                                 ______________________________________                                        2      4        10       40     10    40                                      1      4        40       40     10    100                                     3      <1        4        4      4     4                                      ______________________________________                                    

The MIC determination was carried out in a serial dilution test, in thedilution series 100-40-20-10-4-1 γ/ml of substrate. The following wereused as nutrient substrates:

a. for Dermatophytes: Sabouraud's test medium

b. for yeasts: meat water -- glucose -- bouillon.

The incubation temperature was 28° C, and the incubation time was 24 to96 hours.

The preparations are primarily fungistatic: fungicidal effects can beachieved in vitro with 4-fold to 6-fold higher MIC concentrations.

The in vitro experiments were also carried out with the compounds fromexamples 1, 2 and 3, which can be regarded as representative of theentire class of compounds.

b. Anti-mycotic action in vivo.

1. Experimental canidosis in mice.

White mice -- strain CF₁ -SPF, pellet fodder, water ad libitum -- wereeach intravenously infected with 1 - 5 × 10⁶ Candida albicans cells.Untreated control animals died 3 to 6 days after infection to the extentof 95% from uraemia through multiple abscess formation in the kidneys.

In the case of oral and/or parenteral therapy with the preparationsmentioned -- especially with the compound from example 3 -- in dailydoses of 50 to 200 mg/kg of body weight, divided into two individualdoses, 60 to 90% of the animals survived on the 6th day after theinfection. In these experiments, the therapy was started on the day ofthe infection and continued up to the 5th day after infection.

The preparations are rapidly resorbed after oral administration. Bloodlevel maxima, with concentrations of up to 6 γ/mg of serum, are reached4 to 5 hours after administration. 2. Experimental trichophytia in mice,caused by Trichophyton Quinckaenum.

White CF₁ -SPF mice were infected dorsally with a spore suspension ofTrichophyton Quinckeanum. After 8 to 10 days typical, multiple cupsdeveloped in the untreated control animals.

By means of daily doses of 50 to 200 mg/kg of body weight, divided intotwo individual doses and administered orally from the day of infectionup to the 8th day after infection, it was possible completely tosuppress the occurrence of the cups typical of the infection in infectedanimals. 3. Experimental trichophytia in guinea pigs caused byTrichophyton mentagrophytes.

Guinea pigs, Pearlbright white, weighing 400 to 500 g were infected ontheir shaved back with a spore suspension of Trichophytonmentagrophytes. A deep dermatomycosis developed at the point ofinfection within 21 to 25 days, and continued up to the 30th - 34th dayafter infection.

In the case of animals which were treated locally with a 1% strengthsolution of the preparations in polyethylene glycol 400, once daily fromthe 3rd day after infection to the 14th day after infection, theinfection completely healed within the therapy time. Non-tolerancereactions by the skin were not observable in these experiments.

According to these results, the preparations mentioned can be regardedas good anti-mycotic agents of broad activity, which are curativelyactive both in oral and parenteral administration and in localadministration in animal experiments.

The excellent anti-mycotic activity of the new compounds makes itpossible to employ them in the whole of human medicine and veterinarymedicine.

The following are envisaged as indications for the new preparations:

1. in human medicine:

Dermatomycoses by Dermatophytes, for example varieties of Trichophyton,Microsporon and Epidermophyton, systemic and organic mycoses by, forexample, varieties of Candida, Histoplasma, Cryptococcus andCoccidioides, Aspergilli and other moulds.

2. in veterinary medicine:

Dermatomycoses as well as organic mycoses and systemic mycoses caused byDermatophytes, yeasts, biphase fungi and moulds.

The new compounds can be administered orally, parenterally or locally,as free bases or in the form of their salts with physiologicallytolerated acids.

In general, it has proved advantageous to administer amounts of about 30mg to about 200 mg, preferably about 50 to 100 mg, per kg of body weightper day, to achieve effective results. Nevertheless it can at times benecessary to deviate from the amounts mentioned, in particular dependingon the body weight of the test animal or patient, the nature of themethod of administration, and severity of the condition as well asbecause of the species of animal and its individual behavior towards themedicine, or the patient's past medical history, or the nature of theformulation and the point in time or interval at which theadministration takes place. Thus it can suffice in some cases to useless than the abovementioned minimum amount, while in other cases theupper limit mentioned must be exceeded. Where larger amounts areadministered it can be advisable to divide these into several individualadministrations over the course of the day. The same dosage range isenvisaged for administration in human medicine. The other comments madeabove also apply, in a general sense.

The compounds of the present invention may be formulated intopharmaceutical compositions which comprise a compound according to thepresent invention in combination with a pharmaceutically acceptablenon-toxic inert diluent or carrier. Possible forms for administration,in combination with various inert excipients, are tablets, capsules,powders, sprays, aqueous suspensions, injectable solutions, elixirs,syrups and the like. Such excipients include solid diluents or fillers,a sterile aqueous medium and also various non-toxic organic solvents andthe like. Of course the tablets and the like considered for oraladministration can be provided with a sweetener additive and the like.The therapeutically active compound should, in the abovementioned case,be present at a concentration of about 0.5 to 90 per cent by weight ofthe total mixture, that is to say in amounts which suffice to achievethe abovementioned dosage range.

In the case of oral use, tablets can of course also contain additivessuch as sodium citrate, calcium carbonate and dicalcium phosphate,together with various additional substances, such as starch, preferablypotato starch and the like, and binders such as polyvinylpyrrolidone,gelatines and the like. Furthermore, lubricants such as magnesiumstearate, sodium laurylsulphate and talc can be conjointly used fortablet-making. In the case of aqueous suspensions and/or elixirs whichare intended for oral uses, the active substance can be used togetherwith various flavour-improving agents, dyestuffs and emulsifiers and/ortogether with diluents such as water, ethanol, propylene glycol orglycerine and similar compounds or combinations of this nature.

In the case of parenteral use, solutions of the active substances insesame oil or groundnut oil or in aqueous propylene glycol ofN,N-dimethylformamide can be employed, as can sterile aqueous solutionsin the case of the water-soluble compounds. Such aqueous solutionsshould be buffered in the usual manner where required, and furthermorethe liquid diluent should beforehand be rendered isotonic by addition ofthe requisite amount of salt or glucose. Such aqueous solutions are inparticular suitable for intravenous, intramuscular and interperitonealinjections.

The manufacture of such sterile aqueous media is carried out in a knownmanner.

The compounds are used locally in the form of 0.5 to 5% strength,preferably 1% strength, solutions (for example in dimethylformamide,glycerine or water, alcohol such as ethanol and isopropanol, and buffersolutions), but also as emulsions, suspensions, powders and tablets.

In general, therefore, the invention also provides a pharmaceuticalcomposition comprising as active ingredient at least one of the newactive compounds in admixture with a pharmaceutically acceptablenon-toxic inert solid or liquid diluent or carrier.

The invention further provides a medicament in unit dosage formcomprising as active ingredient at least one of the new active compoundseither alone or in admixture with a pharmaceutically acceptablenon-toxic inert solid or liquid diluent or carrier. The medicament mayinclude a protective envelope containing the active compound and, ifused, the diluent or carrier.

The term "medicament in unit dosage form" as used in the presentspecification means a medicament as defined above in the form ofdiscrete portions each containing a unit dose, or a multiple orsub-multiple of a unit dose of the active compound or compounds,especially a half, a third or a quarter of a unit dose, or two, three orfour unit doses. Such portions may, for example, be in monolithiccoherent form, such as tablets, suppositories, pills or dragees; inwrapped or concealed form, such as wrapped powders, cachets, sachets, orcapsules; in ampoules, either free or as a sterile solution suitable forparenteral injection; or in any other form known to the art.

We claim:
 1. A pharmaceutical composition for treating mycoticinfections in humans and animals which comprises an antimycoticallyeffective amount of a compound of the formula: ##EQU8## or apharmaceutically-acceptable, nontoxic salt thereof, wherein X is a6-membered heteroaromatic moiety of the formula ##SPC14##Y is acylopropyl, cyclohexyl, phenyl unsubstituted or substituted by 1 or 2members selected from the group consisting of fluorine, chlorine, alkylof 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, thioalkyl of 1 to4 carbon atoms, trifluoromethyl and nitro; and Z is pyridyl, phenyl,phenyl substituted by fluorine or chlorine, naphthyl or alkoxycarbonylof 1 to 4 carbon atoms in the alkoxy moiety;in combination with apharmaceutically-acceptable, nontoxic, inert diluent or carrier.
 2. Acomposition according to claim 1 whereinY is phenyl or p-fluorophenyl;and Z is phenyl.
 3. A composition according to claim 1 wherein ##SPC15##4. A compostion according to claim 1 wherein ##SPC16##
 5. A compositionaccording to claim 1 wherein ##SPC17##
 6. A composition according toclaim 1 wherein ##SPC18##
 7. A composition according to claim 1 wherein##SPC19##
 8. A composition according to claim 1 wherein ##SPC20##
 9. Acomposition according to claim 1, wherein the compound is ##SPC21## 10.A composition according to claim 1, wherein the compound is ##SPC22##11. A method of treating mycotic infections in humans and animals whichcomprises administering to a human or animal in need thereof anantimycotically effective amount of a composition of claim
 1. 12. Amethod of treating mycotic infections in humans and animals whichcomprises administering to a human or animal in need thereof anantimycotically effective amount of a composition of claim
 2. 13. Amethod of treating mycotic infections in humans and animals whichcomprises administering to a human or animal in need thereof anantimycotically effective amount of a composition of claim
 3. 14. Amethod of treating mycotic infections in humans and animals whichcomprises administering to a human or animal in need thereof anantimycotically effective amount of a composition of claim
 5. 15. Amethod of treating mycotic infections in humans and animals whichcomprises administering to a human or animal in need thereof anantimycotically effective amount of a composition of claim
 5. 16. Amethod of treating mycotic infections in humans and animals whichcomprises administering to a human or animal in need thereof anantimycotically effective amount of a composition of claim
 6. 17. Amethod of treating mycotic infections in humans and animals whichcomprises administering to a human or animal in need thereof anantimycotically effective amount of a composition of claim
 7. 18. Amethod of treating mycotic infections in humans and animals whichcomprises administering to a human or animal in need thereof anantimycotically effective amount of a composition of claim
 8. 19. Amethod of treating mycotic infections in humans and animals whichcomprises administering to a human or animal in need thereof anantimycotically effective amount of a composition of claim
 9. 20. Amethod of treating mycotic infections in humans and animals whichcomprises administering to a human or animal in need thereof anantimycotically effective amount of a composition of claim 10.